# Liquid Biopsy in Non-Metastatic Prostate Cancer: Clinical Evidence and Future Directions

## TL;DR

This paper reviews how liquid biopsies, specifically ctDNA, may help assess prostate cancer aggressiveness and recurrence risk in non-metastatic cases.

## Contribution

The paper highlights ctDNA's potential as a prognostic marker for non-metastatic prostate cancer, beyond traditional biomarkers.

## Key findings

- Circulating tumor DNA (ctDNA) was linked to biologically aggressive disease and higher recurrence risk.
- CTC detection rates were low in non-metastatic prostate cancer and showed limited prognostic value.
- Tumor-informed assays improved ctDNA detection and clinical relevance.

## Abstract

This review highlights the limited clinical utility of circulating tumor cells (CTCs) and the emerging prognostic relevance of circulating tumor DNA (ctDNA) in non-metastatic prostate cancer. CtDNA may serve as a marker of minimal residual disease and biological aggressiveness, pending validation in prospective trials.

Background and Objective: Liquid biopsy has transformed the management of advanced prostate cancer, yet its clinical role in non-metastatic disease remains uncertain. Conventional biomarkers such as PSA, imaging, and pathology have limited ability to capture minimal residual disease and biological aggressiveness. The objective of this review was to critically evaluate the current evidence on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in non-metastatic prostate cancer, focusing on feasibility, prognostic value, and potential clinical applications. Methods: A narrative review of PubMed-indexed original studies evaluating liquid biopsy in clinically localized or non-metastatic prostate cancer was performed. Eligible studies included patients treated with curative-intent local therapy or experiencing biochemical recurrence without radiologic metastases. Study designs were predominantly prospective or retrospective observational cohorts. Liquid biopsy analytes included CTCs and ctDNA assessed from peripheral blood plasma using EpCAM-based enrichment, targeted next-generation sequencing, whole-genome sequencing, or ultra-sensitive tumor-informed assays. Primary outcomes included detection rates, associations with clinicopathologic features, biochemical recurrence, metastasis-free survival, and overall survival. Key Findings and Limitations: Across 11 studies, CTC detection using EpCAM-based platforms was infrequent in localized disease and biochemical recurrence and showed limited prognostic value (10–11% in preoperative settings). In contrast, ctDNA was detectable in a minority of patients but consistently identified biologically aggressive disease and a higher risk of recurrence when present, particularly using tumor-informed ultra-sensitive assays. Limitations include low detection rates, heterogeneous methodologies, small sample sizes, and predominantly exploratory study designs. Conclusions and Clinical Implications: Currently, its most promising application is not broad screening, but as a selective, biology-driven tool for detecting minimal residual disease and refining risk assessment. CtDNA acts as a biological risk modifier, potentially guiding the escalation or de-escalation of adjuvant therapy. However, prospective biomarker-driven trials are required to validate these strategies before routine clinical implementation.